Gastrin and cholecystokinin (CCK) are physiologically active substances belonging to the gastrointestinal peptide hormone family, which exert various functions by interacting with receptors. Receptors for gastrin are mainly present in parietal cells of fundic glands and those for the latter are classified in two types, i.e., peripheral type (CCK-A receptors) present in peripheral tissues such as digestive gut and central type (CCK-B receptors) present in brain. Inhibitors of such peptide hormones are expected to be useful for preventing and/or treating various disorders caused by the effect of the hormones on digestive gut and/or central nervous system. To achieve an effective prevention and/or treatment, it is necessary to use a compound capable of binding to an aimed peptide hormone receptor in preference, discriminating it from receptors for peptide hormones of different sub-type. For instance, gastrin antagonists specific to gastrin receptors are thought to be effective on gastrin-associated disorders such as peptic ulcers in gaster and duodenum, Zollinger-Ellison syndrome, hyperplasia of sinus G cells, and decrease in gastrin activity. (Taisha, 29/7, 1992, R. Eissele, H. Patberg, H. Koop, W. Krack, W. Lorenz, A. T. McKnight & R. Arnold, Gastroenterology, 103, 1596 (1992), etc.) Antagonists specific to CCK-B receptors are thought to be useful in the reinforcement and elongation of the analgetic effect of opioid-type compounds (e.g., morphine derivatives such as morphine sulfate or hydrochloride) which competitively bind to opioid receptors [Drugs of the future 18, 919 (1993); Proc. Natl. Acad. Sci. U.S.A., Vol. 87, p. 71, 05 Sep. 1990, Neurobiology].
The present applicant has developed certain carbamoylmethylurea derivatives which have selective and potent affinity for gastrin- and/or CCK-B-receptors but have low affinity for CCK-A receptors (WO95/21856). The carbamoylmethylurea derivatives are represented by the formula (I): ##STR4## wherein R.sub.1 is a hydrogen or lower alkyl; R.sub.2 is a hydrogen or --CH.sub.2 COR.sub.5 (R.sub.5 is lower alkoxy, lower alkylamino, cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic group); R.sub.3 is an optionally substituted phenyl; R.sub.4 is an optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkyl or optionally substituted heterocyclic group. Compounds wherein R.sub.2 is --CH.sub.2 COR.sub.5 have especially potent pharmacological activity and are useful as anti-ulcer agent, and those wherein R.sub.2 is hydrogen is also useful as an intermediate.
For the clinical application of the compounds (I) in the treatment and prevention of various diseases, it is essential to establish a measure for supplying them stably. However, conventional preparation methods such as those described in WO91/12264, U.S. Pat. No. 5,223,529, WO91/12265, WO91/13907, WO91/13874, WO91/13862, WO93/01167, WO94/15914, WO94/15955 involve complicated procedures including protection of aromatic carboxyl group, deprotection, etc., and are not suited for the industrial production of the compounds (I). Accordingly, there has been a strong demand for the development of a method which affords the compounds (I) more efficiently and simply, thereby contributing to the establishment of stable supply of the compounds (I), and also to the clinical application thereof.